Glutaryl-coenzyme A dehydrogenase (GCDH) deficiency is an inherited disorder of lysine and tryptophan metabolism known as glutaric acidemia type I (GA-I). Affected children develop striatal degeneration similar to Huntington's disease. However, the brain injury of GA-1 presents acutely during a period of susceptibility between 5 and 18 months of age and is commonly preceded by the catabolic state of illness or fasting. The mechanism of injury remains unknown. Current treatment consists of lysine restriction to limit glutaric acid producing substrate. Unfortunately, protection is incomplete and one-third of affected children develop striatal injuries regardless of treatment efforts. Tremendous financial and emotional costs are associated with caring for the children injured from GA-I, which may be a treatable disorder. In order to study the pathophysiology of GA-I and design better treatments, we developed a mouse model using GCDH-deficient (Gcdh-/-) mice exposed to increased dietary lysine that shows striking similarities to human GA-I. In this model, weanling but not adult Gcdh-/- mice accumulate substantial brain glutaric acid levels that correlate with severe brain injury. Age-dependent susceptibility in this model was shown to be associated with developmental differences in brain amino acid utilization. Brain injury in weanling but not adult mice was preceded by enhanced accumulation of lysine and then glutaric acid at the same time 1-ketoglutarate and glutamate were both depleted. Dietary intervention with atypical amino acid, homoarginine and glucose together was effective in reducing brain lysine and glutaric acid accumulation, which prevented injury in susceptible weanling Gcdh- /- mice. However, the use of homoarginine for human consumption poses a formidable regulatory challenge. Therefore, alternatives that have been determined safe for human use need to be identified and tested for potential treatment development. This is a proposal that brings together a multidisciplinary team to study the molecular mechanism of GA-I encephalopathy and use this information to identify safe, effective treatment strategies to prevent these striatal injuries. PUBLIC HEALTH RELEVANCE: This project represents an opportunity to develop protective treatments for glutaric aciduria that may be relevent to other childhood metabolic disorders.